A genome-wide association study of Chinese and English language phenotypes in Hong Kong Chinese children.

Dyslexia and developmental language disorders are important learning difficulties. However, their genetic basis remains poorly understood, and most genetic studies were performed on Europeans. There is a lack of genome-wide association studies (GWAS) on literacy phenotypes of Chinese as a native language and English as a second language (ESL) in a Chinese population. In this study, we conducted GWAS on 34 reading/language-related phenotypes in Hong Kong Chinese bilingual children (including both twins and singletons; total N = 1046). We performed association tests at the single-variant, gene, and pathway levels. In addition, we tested genetic overlap of these phenotypes with other neuropsychiatric disorders, as well as cognitive performance (CP) and educational attainment (EA) using polygenic risk score (PRS) analysis. Totally 5 independent loci (LD-clumped at r2 = 0.01; MAF > 0.05) reached genome-wide significance (p < 5e-08; filtered by imputation quality metric Rsq>0.3 and having at least 2 correlated SNPs (r2 > 0.5) with p < 1e-3). The loci were associated with a range of language/literacy traits such as Chinese vocabulary, character and word reading, and rapid digit naming, as well as English lexical decision. Several SNPs from these loci mapped to genes that were reported to be associated with EA and other neuropsychiatric phenotypes, such as MANEA and PLXNC1. In PRS analysis, EA and CP showed the most consistent and significant polygenic overlap with a variety of language traits, especially English literacy skills. To summarize, this study revealed the genetic basis of Chinese and English abilities in a group of Chinese bilingual children. Further studies are warranted to replicate the findings.

Effect and Safety of Herbal Medicine Foot Baths in Patients with Diabetic Peripheral Neuropathy: A Multicenter Double-Blind Randomized Controlled Trial.

OBJECTIVE: To evaluate the effect and safety of foot baths with Tangbi Waixi Decoction (TW) in treating patients with diabetic peripheral neuropathy (DPN). METHODS: It is a multicenter double-blinded randomized controlled trial. Participants with DPN were recruited between November 18, 2016 and May 30, 2018 from 8 hospitals in China. All patients received basic treatments for glycemic management. Patients received foot baths with TW herbal granules either 66.9 g (intervention group) or 6.69 g (control group) for 30 min once a day for 2 weeks and followed by a 2-week rest, as a therapeutic course. If the Toronto Clinical Scoring System total score (TCSS-TS) ⩾6 points, the patients received a total of 3 therapeutic courses (for 12 weeks) and were followed up for 12 weeks. The primary outcome was change in TCSS-TS score at 12 and 24 weeks. Secondary outcomes included changes in bilateral motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV) of the median and common peroneal nerve. Safety was also assessed. RESULTS: Totally 632 patients were enrolled, and 317 and 315 were randomized to the intervention and control groups, respectively. After the 12-week intervention, patients in both groups showed significant declines in TCSSTS scores, and significant increases in MNCV and SNCV of the median and common peroneal nerves compared with pre-treatment (P<0.05). The reduction of TCSS-TS score at 12 weeks and the increase of SNCV of median nerve at 24 weeks in the control group were greater than those in the intervention group (P<0.05). The number of adverse events did not differ significantly between groups (P>0.05), and no serious adverse event was related with treatment. CONCLUSION: Treatment of TW foot baths was safe and significantly benefitted patients with DPN. A low dose of TW appeared to be more effective than a high dose. (Registry No. ChiCTR-IOR-16009331).

Scrutinizing science to save lives: uncovering flaws in the data linking L-type calcium channels blockers to CRAC channels and heart failure.

Hypertension is estimated to affect almost 1 billion people globally and significantly increases risk of myocardial infarction, heart failure, stroke, retinopathy and kidney disease. One major front line therapy that has been used for over 50 years involves L-type Ca 2+ channel blockers (LCCBs). One class of LCCBs is the dihydropyridine family, with amlodipine being widely prescribed regardless of gender, race, ethnicity or age. In 2020, Johnson et al. 7 reported that all LCCBs significantly increased the risk of heart failure, and attributed this effect to non-canonical activation of store-operated Ca 2+ entry. A major approach on which they based many of their arguments was to measure cytosolic Ca 2+ using the fluorescent Ca 2+ indicator dye fura-2. We recently demonstrated that amlodipine is highly fluorescent within cells and overwhelms the fura-2 signal, precluding the use of the indicator dye with amlodipine 24 . Our meta-analyses and prospective real world study showed that dihydropyridines were not associated with an increase in heart failure, likely explained by the lack of consideration by Johnson et al. 7 of well-known confounding factors such as age, race, obesity, prior anti-hypertensive treatment or diabetes 24 . Trebak and colleagues have responded to our paper with a forthright and unwavering defence of their work 27 . In this paper, we carry out a forensic dissection of Johnson et al., 7 and conduct new experiments that address directly points raised by Trebak et al. 27 . We show that there are major flaws in the design and interpretation of their key experiments, that fura-2 cannot be used with amlodipine, that there are fundamental mathematical misunderstandings and mistakes throughout their study leading to critical calculations on heart failure that are demonstrably wrong, and several of their own results are inconsistent with their interpretation. We therefore believe the study by Johnson et al. 7 is flawed at many levels and we stand by our conclusions.

Hypofractionated radiotherapy for refractory or relapsed aggressive B-cell lymphoma in the rituximab era.

BACKGROUND: Radiotherapy (RT) is an effective and available local treatment for patients with refractory or relapsed (R/R) aggressive B-cell lymphomas. However, the value of hypofractionated RT in this setting has not been confirmed. METHODS: We retrospectively analyzed patients with R/R aggressive B-cell lymphoma who received hypofractionated RT between January 2020 and August 2022 at a single institution. The objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and acute side effects were analyzed. RESULTS: A total of 30 patients were included. The median dose for residual disease was 36 Gy, at a dose per fraction of 2.3-5 Gy. After RT, the ORR and complete response (CR) rates were 90% and 80%, respectively. With a median follow-up of 10 months (range, 2-27 months), 10 patients (33.3%) experienced disease progression and three died. The 1-year OS and PFS rates for all patients were 81.8% and 66.3%, respectively. The majority (8/10) of post-RT progressions involved out-of-field relapses. Patients with relapsed diseases, no response to systemic therapy, multiple lesions at the time of RT, and no response to RT were associated with out-of-field relapses. PFS was associated with response to RT (P = 0.001) and numbers of residual sites (P < 0.001). No serious non-hematological adverse effects (≥ grade 3) associated with RT were reported. CONCLUSION: These data suggest that hypofractionated RT was effective and tolerable for patients with R/R aggressive B-cell lymphoma, especially for those that exhibited localized residual disease.

The alleviating effect of Scutellaria amoena extract on the regulation of gut microbiota and its metabolites in NASH rats by inhibiting the NLRP3/ASC/caspase-1 axis.

Background: Scutellaria amoena (SA) is the root of S. amoena C.H. Wright of Labiatae, also known as Scutellaria southwestern. This is mainly distributed in Sichuan, Yunnan, and Guizhou in China. In southwest China, SA is used as an alternative method to genuine medicine for the treatment of allergy, diarrhea, inflammation, hepatitis, and bronchitis. Thus far, studies on the effects of SA on non-alcoholic steatohepatitis (NASH) are lacking. This paper investigated the effect of SA on the regulation of gut microbiota and its metabolites in NASH rats by inhibiting the NOD-like receptor 3 (NLRP3)/apoptosis-associated speck-like protein (ASC)/caspase-1 axis. Methods: A NASH rat model was induced by a high-fat diet (HFD) for 12 weeks, and rats were orally given different doses of SA extracts (150 and 300 mg/kg/d) for 6 weeks. Changes in histological parameters, body weight, organ indexes, cytokines, and biochemical parameters related to NLRP3 in NASH rats were checked. 16S rRNA gene sequencing and UPLC-MS/MS technology were used to analyze the changes in the gut microbiota composition and its metabolites in NASH rats. Results: SA significantly inhibited the HFD-induced increase in body weight, lipid levels, and inflammatory infiltration. SA notably inhibited the HFD-induced increase in the upper and lower factors of NLRP3, such as transforming growth factor (TGF)-ß, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-18, pro-IL-18, IL-1ß, pro-IL-1ß, NLRP3, ASC, and caspase-1. Additionally, mRNA expressions of caspase-1, NLRP3, and ASC were significantly downregulated after SA treatment. The results of the intestinal flora showed that SA could increase the diversity of flora and change its structure and composition in NASH rats by reducing Firmicutes/Bacteroidetes (F/B) ratio, Blautia (genus), Lachospiraceae (family), and Christensenellaceae R-7 group (genus), and increasing Muribaculaceae (family) and Bacteroides (genus). The metabolomics revealed that 24 metabolites were possibly the key metabolites for SA to regulate the metabolic balance of NASH rats, including chenodeoxycholic acid, xanthine, and 9-OxoODE. Nine metabolic pathways were identified, including primary bile acid biosynthesis, bile secretion, purine metabolism, and secondary bile acid biosynthesis. Conclusion: SA can regulate the intestinal microbial balance and metabolic disorder by inhibiting the NLRP3/ASC/caspase-1 axis to relieve NASH.

Efficacy of a self-management program on quality of life in colorectal cancer patients: A randomized controlled trial.

PURPOSE: To test the efficacy of a self-management program based on acceptance and commitment therapy on quality of life, emotional distress, fatigue, physical activity, and fruit and vegetable intake in patients with colorectal cancer. METHODS: The study was a randomized controlled trial. A sample of 156 patients with colorectal cancer (stage I-III) was recruited by convenience sampling and participants were allocated randomly assigned to control or intervention groups. The intervention included a colorectal cancer self-management information booklet, two personal skills training sessions, and 12 follow-up telephone calls. The control group received health education leaflets. Outcome variables were assessed in both groups at baseline and every two months thereafter during the six-month follow-up period. RESULT: The mean age of participants was 62 years (range: 30-89 years). Generalized estimation equations analyses revealed significant differences over time in changes in anxiety (ß = -2.22, p = 0.001), depression (ß = -1.48, p = 0.033), fatigue (ß = 4.46, p = 0.001), physical and functional measures (ß = 6.16, p = 0.005), and colorectal-cancer-specific quality of life (ß = 7.45, p = 0.012). However, there were no significant differences in changes in physical activity or fruit and vegetable intake over time. CONCLUSION: The self-management skills provided by oncology nurses, including symptom management, psychological adjustment, and relaxation exercises, help colorectal cancer patients to overcome the challenges of cancer survivorship, accelerate their recovery, and improve their quality of life. THE TRIAL NUMBER: NCT03853278 registered on ClinicalTrials.gov.

Effects of coping on nurses' mental health during the COVID-19 pandemic: Mediating role of social support and psychological resilience.

BACKGROUND: Fighting against the COVID-19 pandemic, front-line nurses were under unprecedented psychological pressure. Therefore, it is necessary to promptly evaluate the psychological status of nurses during the COVID-19 epidemic period. AIM: To investigate nurses' mental health during the COVID-19 pandemic, and to test the mediating role of social support and psychological resilience between coping and mental health. DESIGN: This was a descriptive, cross-sectional survey which used a structural equation model. METHOD: In total, 711 registered nurses were included. All participants were invited to complete a socio-demographic questionnaire, the general health questionnaire, the trait coping style questionnaire, the perceived social support scale and the Conner-Davidson Resilience scale. RESULTS: In total, 50.1% nurses had high risk of mental health. Positive coping positively affected social support and psychological resilience, while it negatively affected mental health. Negative coping negatively affected social support and psychological resilience, while it positively affected mental health. Social support positively affected psychological resilience, while it negatively affected mental health. In addition, social support mediated coping and psychological resilience, and coping and mental health. Moreover, psychological resilience negatively affected mental health, and it mediated coping and mental health.

Effects of Tylophora yunnanensis Schltr on regulating the gut microbiota and its metabolites in non-alcoholic steatohepatitis rats by inhibiting the activation of NOD-like receptor protein 3.

ETHNOPHARMACOLOGICAL RELEVANCE: Tylophora yunnanensis Schltr (TYS) is widely distributed in Yunnan, Guizhou, and other places in China. It is commonly used by folks to treat hepatitis and other liver-related diseases; however, its mechanism of action is still unclear. AIM OF THE STUDY: This study aimed to determine the effects of TYS on regulating gut microbiota and its metabolites in non-alcoholic steatohepatitis (NASH) rats by inhibiting the activation of NOD-like receptor protein3 (NLRP3). MATERIAL AND METHODS: An HFD-induced rat model was established to investigate if the intragastric administration of TYS could mediate gut microbiota and their metabolites to ultimately improve the symptoms of NASH. The improving effects of TYS on NASH rats were assessed by measuring their body weight, lipid levels, histopathology, and inflammatory factor levels in the rat models. The regulatory effects of TYS on NLRP3 in the NASH rats were analyzed using real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), which determined the levels of NLRP3-related factors. The changes in the composition of the gut microbiota of NASH rats were analyzed using 16S rRNA gene sequencing technology. Meanwhile, the Ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used for the non-targeted analysis of metabolites in the cecum contents. RESULTS: The results showed that TYS could improve NASH by decreasing the body weight and levels of lipid, AST, ALT, LPS, FFA, VLDL, IL-1ß, IL-6, TNF-α, TGF-ß, NLRP3, ASC, and Caspase-1 in the NASH rats. The analysis of gut microbiota showed that TYS could improve the diversity and abundance of gut microbiota and alter their composition by decreasing the Firmicutes/Bacteroidetes (F/B) ratio and relative abundances of Lachnospiraceae, Christensenellaceae, Blautia, etc. while increasing those of Muribaculaceae, Rumiaococcus, Ruminococcaceae, etc. The analysis of metabolites in the cecum contents suggested that the arachidonic acid metabolism, bile secretion, serotonergic synapse, Fc epsilon RI signaling pathway, etc. were regulated by TYS. The metabolites enriched in these pathways mainly included chenodeoxycholic acid, prostaglandin D2, TXB2, 9-OxoODE, and 13(S)-HOTrE. CONCLUSIONS: These findings suggested that TYS could alleviate the NASH symptoms by decreasing the body weight, regulating the lipid levels, reducing the inflammatory response, and inhibiting the expression levels of NLRP3, ASC, and Caspase-1 in the NASH rats. The changes in the composition of gut microbiota and their metabolic disorder were closely related to the activation of NLRP3. TYS could significantly inhibit the activation of NLRP3 and regulate the composition of gut microbiota and the disorder of metabolites during NASH modeling.

Flavonoids from Scutellaria amoena C. H. Wright alleviate mitochondrial dysfunction and regulate oxidative stress via Keap1/Nrf2/HO-1 axis in rats with high-fat diet-induced nonalcoholic steatohepatitis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is among the most common liver diseases in the world. Flavonoids from Scutellaria amoena (SAF) are used in the treatment of hepatopathy in China. However, the effect and mechanism against NASH remain unclear. We investigated the alleviating effect of SAF on NASH via regulating mitochondrial dysfunction and oxidative stress. METHODS: The effects of SAF on NASH were evaluated using in vitro and in vivo methods. L02 cells were induced by fat emulsion to establish an adipocytes model, followed by treatment with SAF for 24 h. NASH rat models were established by the administration of a high-fat diet for 12 weeks and were administered SAF for six weeks. Changes in body weight, organ indexes, lipid levels, inflammatory cytokines, mitochondrial indicators, and fatty acid metabolism were investigated. RESULTS: SAF significantly improved body weight, organ indexes, lipid levels, liver injury, and inflammatory infiltration in NASH rats. SAF notably regulated interleukin-6, tumor necrotic factor-alpha, superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), kelch-like ECH-associated protein 1 (Keap1), nuclear factor-erythroid factor 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). Additionally, SAF improved mitochondrial dysfunction, increased the levels of GSH, SOD, ATP synthase, complex I and II, and decreased the level of MDA in liver mitochondria. SAF regulated the expression of ß-oxidation genes, including peroxisome proliferator-activated receptor -gamma coactivator-1alpha (PGC-1α), carnitine palmitoyltransferase-1 (CPT1) A, CPT1B, medium-chain acyl-CoA dehydrogenase, long-chain acyl-CoA dehydrogenase, very long-chain acyl-CoA dehydrogenase, and PPARα. CONCLUSION: SAF can alleviate NASH by regulating mitochondrial function and oxidative stress via the Keap1/Nrf2/HO-1 axis.

Nuanced Interactions between AKAP79 and STIM1 with Orai1 Ca2+ Channels at Endoplasmic Reticulum-Plasma Membrane Junctions Sustain NFAT Activation.

A-kinase anchoring protein 79 (AKAP79) is a human scaffolding protein that organizes Ca2+/calmodulin-dependent protein phosphatase calcineurin, calmodulin, cAMP-dependent protein kinase, protein kinase C, and the transcription factor nuclear factor of activated T cells (NFAT1) into a signalosome at the plasma membrane. Upon Ca2+ store depletion, AKAP79 interacts with the N-terminus of STIM1-gated Orai1 Ca2+ channels, enabling Ca2+ nanodomains to stimulate calcineurin. Calcineurin then dephosphorylates and activates NFAT1, which then translocates to the nucleus. A fundamental question is how signalosomes maintain long-term signaling when key effectors are released and therefore removed beyond the reach of the activating signal. Here, we show that the AKAP79-Orai1 interaction is considerably more transient than that of STIM1-Orai1. Free AKAP79, with calcineurin and NFAT1 in tow, is able to replace rapidly AKAP79 devoid of NFAT1 on Orai1, in the presence of continuous Ca2+ entry. We also show that Ca2+ nanodomains near Orai1 channels activate almost the entire cytosolic pool of NFAT1. Recycling of inactive NFAT1 from the cytoplasm to AKAP79 in the plasma membrane, coupled with the relatively weak interaction between AKAP79 and Orai1, maintain excitation-transcription coupling. By measuring rates for AKAP79-NFAT interaction, we formulate a mathematical model that simulates NFAT dynamics at the plasma membrane.

Efficacy of flavonoids-containing supplements on insulin resistance and associated metabolic risk factors in overweight and obese subjects: a systematic review and meta-analysis of 25 randomized controlled trials.

Background: Obesity is becoming a global epidemic. Flavonoids, with anti-inflammatory and antioxidative functions, are proposed to treat insulin resistance (IR) in obese subjects. We aimed to evaluate the effectiveness and safety of flavonoids-containing supplements on IR and associated metabolic risk factors in overweight and obese participants. Methods: Randomized controlled trials (RCTs) involving flavonoids-containing supplements used to treat overweight and obese subjects with results of IR, other associated metabolic risk factors, and adverse effects published were retrieved from 5 electronic databases from the year of inception to January 2, 2022. Results: Twenty-five RCTs (n = 1950) were included. Pooled results demonstrated that HOMA-IR in the group receiving flavonoids-containing supplements significantly decreased versus the control group (WMD = -0.132, 95% CI: -0.236 to -0.027, p = 0.013). Subgroup analyses showed that HOMA-IR in the subgroup receiving flavonoid-containing mixtures significantly decreased (WMD = -0.25, 95% CI: -0.43 to -0.06, p = 0.008), whereas such result was not found in the singly-used flavonoids subgroup (WMD = -0.08, 95% CI: -0.20 to 0.05, p = 0.240). In addition, QUICKI in the experimental group had an increasing trend compared to that in the control group (WMD = 0.01, 95% CI: -0.00 to 0.02, p = 0.065). For secondary outcomes, FBG, FBI, TC, TG, SBP, weight, BMI, and WHR in the group receiving flavonoids-containing supplements dropped significantly compared to those in the controls (WMD = -0.05, 95% CI: -0.08 to -0.02, p = 0.002; WMD = -0.58, 95% CI: -1.04 to -0.12, p = 0.014; WMD = -0.04, 95% CI: -0.06 to -0.03, p < 0.001; WMD = -0.04, 95% CI: -0.05 to -0.03, p < 0.001; WMD = -2.01, 95% CI: -3.17 to -0.86, p = 0.001; WMD = -0.29, 95% CI: -0.49 to -0.09, p = 0.004; WMD = -0.10 95% CI: -0.17 to -0.04, p = 0.003; WMD = -0.10, 95% CI: -0.01 to -0.00, p = 0.015; respectively). Adverse reactions did not differ between the group receiving flavonoids-containing supplements and the control group (RR = 0.97, 95% CI: 0.62 to 1.52, p = 0.905). Conclusion: This study showed that flavonoids-containing supplements may be efficacious and safe in improving IR and associated metabolic risk factors in overweight and obese participants. Nevertheless, doubt over the findings remains because limited RCTs per type of flavonoids-containing supplement were investigated, and many of the RCTs had a small sample size. Therefore, the findings must be validated in future research. Systematic Review Registration: https://inplasy.com/inplasy-2022-2-0011/, identifier INPLASY202220011.

Flavonoid-containing supplements for preventing acute respiratory tract infections: A systematic review and meta-analysis of 20 randomized controlled trials.

BACKGROUND: This systematic review and meta-analysis was conducted to investigate the efficacy and safety of flavonoid-containing supplements in preventing acute respiratory tract infection (ARTI). METHODS: Randomized controlled trials (RCTs) investigating the effects of flavonoid-containing supplements on ARTI prevention in the aspects of ARTI incidence, mean ARTI sick days, symptoms, bio-immune markers, and adverse effects were searched in 5 databases. Data were searched from inception to November 26, 2021. Stata 16.0 was used to perform the meta-analysis. RESULTS: Twenty RCTs (n = 4521) were included in this systematic review and meta-analysis. Pooled results showed that in the flavonoid-containing supplement group, the ARTI incidence and mean ARTI sick days were significantly decreased compared to those in the control group (RR = 0.81, 95% CI: 0.74-0.89, p < 0.001; WMD = -0.56, 95% CI: -1.04 to -0.08, p = 0.021; respectively). In 8 RCTs, flavonoids were singly used for interventions, ARTI incidence in the experimental group significantly decreased compared to that in the control group (RR = 0.85, 95% CI: 0.72-1.00, p = 0.047). In ten RCTs, flavonoid-containing mixtures were applied for interventions, and ARTI incidence in the experimental group significantly decreased compared to that in the control group (RR = 0.79, 95% CI: 0.71-0.89, p < 0.001). Furthermore, the ARTI incidence and mean ARTI sick days were significantly decreased in the experimental group compared to those in the control group in the flavan-3-ols subgroup (RR = 0.79, 95% CI: 0.67-0.92, p = 0.002; WMD = -2.75, 95% CI: -4.30 to -1.21, p < 0.001; respectively) and the multiple subclasses subgroup (RR = 0.75, 95% CI: 0.63-0.88, p = 0.001; WMD = -0.56, 95% CI: -1.11 to -0.01, p = 0.046; respectively). However, the bio-immune markers including interleukin-6, hypersensitive-c-reactive-protein, tumor necrosis factor-α, and interferon-γ did not differ between the flavonoid group and the control group. Moreover, in the flavonoid-containing supplement group, the incidence of adverse reactions did not increase compared to that in the control group (RR = 1.16, 95% CI: 0.78-1.73, p = 0.469). CONCLUSIONS: This systematic review and meta-analysis showed that flavonoid-containing supplements were efficacious and safe in preventing ARTIs. The most important limitations result from the small number of trials, poor quality of some included RCTs, differences in the composition and types of interventions, principal subclasses of flavonoids, methods of administration, and methodology. Moreover, only a few RCTs conducted independent verification of the flavonoid supplements used in the trial in terms of purity and potency, which may lead to a potential source of bias. Thus, larger and better-designed studies are needed to further verify this conclusion.

Two Novel Flavonoids with Lipid-Lowering Activity from Yi Medicine Shekaqi.

Yi medicine Shekaqi is the most attractive traditional ethnic medicine due to its significant and diverse pharmacological activities. Two novel flavonoids, including 5,2'-dihydroxy-6-methoxy-7-decyloxyflavone and tenaxin II-7-O-ß-D-glucuronopyranosyl acid butyl ester, along with six known flavonoids, were isolated from Yi medicine Shekaqi. Their structures were elucidated based on the analysis of their comprehensive spectral data. The in vitro lipid-lowering activities of the eight compounds showed that all the compounds significantly inhibited the lipopolysaccharide (LPS)-induced increase in the total cholesterol (TC) level, while compounds 1, 4, 6, 7, and 8 significantly inhibited the LPS-induced increase in the triglyceride (TG) level.

Correlation of obesity, dietary patterns, and blood pressure with uric acid: data from the NHANES 2017-2018.

BACKGROUND: Prevalence rates of hyperuricemia and gout are increasing. Clinical investigations of hyperuricemia-related risk factors aid in the early detection, prevention, and management of hyperuricemia and gout. Ongoing research is examining the association of obesity, dietary patterns, and blood pressure (BP) with serum uric acid (sUA). METHODS: A cross-sectional study was conducted based on the National Health and Nutrition Examination Survey. The exposures included body mass index (BMI), dietary patterns, and BP. The outcome variable was sUA level. The weighted multivariate linear regression models and smooth curve fittings were used to assess the association of BMI, dietary patterns, and BP with sUA. RESULTS: There was a significantly positive correlation between BMI and sUA (ß = 0.059, 95% CI: 0.054 to 0.064, P < 0.00001). Overweight and obese individuals had higher sUA levels than those with the normal BMI (ß = 0.451, 95% CI: 0.357 to 0.546, P < 0.00001; ß = 0.853, 95% CI: 0.760 to 0.946, P < 0.00001; respectively). Dietary energy intake was positively correlated with sUA (ß = 0.000, 95% CI: 0.000 to 0.000, P = 0.01057). Dietary intake of carbohydrate and fiber were negatively correlated with sUA (ß = - 0.001, 95% CI: - 0.002 to - 0.000, P < 0.00001; ß = - 0.008, 95% CI: - 0.011 to - 0.004, P = 0.00001; respectively). Moreover, systolic BP was positively correlated with sUA (ß = 0.006, 95% CI: 0.003 to 0.009, P = 0.00002). However, no statistical differences were found about the associations of dietary intake of total sugars, protein, total fat, cholesterol, and diastolic BP with sUA. CONCLUSIONS: The current cross-sectional investigation of a nationally representative sample of US participants showed that BMI, dietary energy intake, and systolic BP were positively correlated with sUA levels; dietary carbohydrate and fiber intake were negatively correlated with sUA levels. The findings might be helpful for the management and treatment of hyperuricemia and gout.

Flavonoids for Treating Viral Acute Respiratory Tract Infections: A Systematic Review and Meta-Analysis of 30 Randomized Controlled Trials.

BACKGROUND: This meta-analysis aimed to investigate the efficacy and safety of flavonoids in treating viral acute respiratory tract infections (ARTIs). METHODS: Randomized controlled trials (RCTs) were entered into meta-analyses performed separately for each indication. Efficacy analyses were based on changes in disease-specific symptom scores. Safety was analyzed based on the pooled data from all eligible trials, by comparing the incidence of adverse events between flavonoids and the control. RESULTS: In this study, thirty RCTs (n = 5,166) were included. In common cold, results showed that the flavonoids group decreased total cold intensity score (CIS), the sum of sum of symptom intensity differences (SSID) of CIS, and duration of inability to work vs. the control group. In influenza, the flavonoids group improved the visual analog scores for symptoms. In COVID-19, the flavonoids group decreased the time taken for alleviation of symptoms, time taken for SARS-CoV-2 RT-PCR clearance, the RT-PCR positive subjects at day 7, time to achievement of the normal status of symptoms, patients needed oxygen, patients hospitalized and requiring mechanical ventilation, patients in ICU, days of hospitalization, and mortality vs. the control group. In acute non-streptococcal tonsillopharyngitis, the flavonoids group decreased the tonsillitis severity score (TSS) on day 7. In acute rhinosinusitis, the flavonoids group decreased the sinusitis severity score (SSS) on day 7, days off work, and duration of illness. In acute bronchitis, the flavonoids group decreased the bronchitis severity score (BSS) on day 7, days off work, and duration of illness. In bronchial pneumonia, the flavonoids group decreased the time to symptoms disappearance, the level of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α). In upper respiratory tract infections, the flavonoids group decreased total CIS on day 7 and increased the improvement rate of symptoms. Furthermore, the results of the incidence of adverse reactions did not differ between the flavonoids and the control group. CONCLUSION: Results from this systematic review and meta-analysis suggested that flavonoids were efficacious and safe in treating viral ARTIs including the common cold, influenza, COVID-19, acute non-streptococcal tonsillopharyngitis, acute rhinosinusitis, acute bronchitis, bronchial pneumonia, and upper respiratory tract infections. However, uncertainty remains because there were few RCTs per type of ARTI and many of the RCTs were small and of low quality with a substantial risk of bias. Given the limitations, we suggest that the conclusions need to be confirmed on a larger scale with more detailed instructions in future studies.Systematic Review Registration: inplasy.com/inplasy-2021-8-0107/, identifier: INPLASY20218010.

AKAP79 Orchestrates a Cyclic AMP Signalosome Adjacent to Orai1 Ca2+ Channels.

To ensure specificity of response, eukaryotic cells often restrict signalling molecules to sub-cellular regions. The Ca2+ nanodomain is a spatially confined signal that arises near open Ca2+ channels. Ca2+ nanodomains near store-operated Orai1 channels stimulate the protein phosphatase calcineurin, which activates the transcription factor NFAT1, and both enzyme and target are initially attached to the plasma membrane through the scaffolding protein AKAP79. Here, we show that a cAMP signalling nexus also forms adjacent to Orai1. Protein kinase A and phosphodiesterase 4, an enzyme that rapidly breaks down cAMP, both associate with AKAP79 and realign close to Orai1 after stimulation. PCR and mass spectrometry failed to show expression of Ca2+-activated adenylyl cyclase 8 in HEK293 cells, whereas the enzyme was observed in neuronal cell lines. FRET and biochemical measurements of bulk cAMP and protein kinase A activity consistently failed to show an increase in adenylyl cyclase activity following even a large rise in cytosolic Ca2+. Furthermore, expression of AKAP79-CUTie, a cAMP FRET sensor tethered to AKAP79, did not report a rise in cAMP after stimulation, despite AKAP79 association with Orai1. Hence, HEK293 cells do not express functional active Ca2+-activated adenylyl cyclases including adenylyl cyclase 8. Our results show that two ancient second messengers are independently generated in nanodomains close to Orai1 Ca2+ channels.

Type C Behavior and Associated Factors in Patients with Breast Cancer During Postoperative Chemotherapy: A Cross-Sectional Study.

BACKGROUND: Type C behavior is a cancer-prone behavior that can affect the occurrence and development of cancer. This study aimed to investigate the prevalence of type C behavior in patients with breast cancer during postoperative chemotherapy and determine its associated factors. METHODS: This study enrolled 161 patients with breast cancer who received postoperative chemotherapy. Type C personality behavior pattern questionnaire was used to assess type C behavior patterns. The following instruments were employed: medical coping modes questionnaire, social support scale, social relational quality scale, Herth hope index. logistic regression was used to identify the factors affecting type C behavior. RESULTS: The incidence of type C behavior was 28%. Participants aged 45-59 years (OR = 3.62, 95% CI = 1.04-12.56, P = 0.043), and who adopted a resignation coping style (OR = 1.25, 95% CI = 1.03-1.50, P = 0.021), were more likely to develop type C behavior. Type C behavior was less common in patients with employment (OR = 0.38, 95% CI = 0.15-0.97, P = 0.043), with a high level of social support (OR = 0.89, 95% CI= 0.80-0.98, P = 0.023), and more hope (OR = 0.83, 95% CI = 0.71-0.98, P = 0.079). CONCLUSION: In this study, 28% patients with breast cancer during postoperative chemotherapy exhibited type C behavior. Associated factors with type C behavior were identified, which could guide health care professionals to reduce the prevalence of type C behavior through guiding patients to adopt positive coping styles and improving their level of social support and hope, especially in those aged 45 to 59 years or in those without employment.

The N terminus of Orai1 couples to the AKAP79 signaling complex to drive NFAT1 activation by local Ca2+ entry.

To avoid conflicting and deleterious outcomes, eukaryotic cells often confine second messengers to spatially restricted subcompartments. The smallest signaling unit is the Ca2+ nanodomain, which forms when Ca2+ channels open. Ca2+ nanodomains arising from store-operated Orai1 Ca2+ channels stimulate the protein phosphatase calcineurin to activate the transcription factor nuclear factor of activated T cells (NFAT). Here, we show that NFAT1 tethered directly to the scaffolding protein AKAP79 (A-kinase anchoring protein 79) is activated by local Ca2+ entry, providing a mechanism to selectively recruit a transcription factor. We identify the region on the N terminus of Orai1 that interacts with AKAP79 and demonstrate that this site is essential for physiological excitation-transcription coupling. NMR structural analysis of the AKAP binding domain reveals a compact shape with several proline-driven turns. Orai2 and Orai3, isoforms of Orai1, lack this region and therefore are less able to engage AKAP79 and activate NFAT. A shorter, naturally occurring Orai1 protein that arises from alternative translation initiation also lacks the AKAP79-interaction site and fails to activate NFAT1. Interfering with Orai1-AKAP79 interaction suppresses cytokine production, leaving other Ca2+ channel functions intact. Our results reveal the mechanistic basis for how a subtype of a widely expressed Ca2+ channel is able to activate a vital transcription pathway and identify an approach for generation of immunosuppressant drugs.

A framework to decipher the genetic architecture of combinations of complex diseases: applications in cardiovascular medicine.

MOTIVATION: Currently, most genome-wide association studies (GWAS) are studies of a single disease against controls. However, an individual is often affected by more than one condition. For example, coronary artery disease (CAD) is often comorbid with type 2 diabetes mellitus (T2DM). Similarly, it is clinically meaningful to study patients with one disease but without a related comorbidity. For example, obese T2DM may have different pathophysiology from nonobese T2DM. RESULTS: We developed a statistical framework (CombGWAS) to uncover susceptibility variants for comorbid disorders (or a disorder without comorbidity), using GWAS summary statistics only. In essence, we mimicked a case-control GWAS in which the cases are affected with comorbidities or a disease without comorbidity. We extended our methodology to analyze continuous traits with clinically meaningful categories (e.g. lipids), and combination of more than two traits. We verified the feasibility and validity of our method by applying it to simulated scenarios and four cardiometabolic (CM) traits. In total, we identified 384 and 587 genomic risk loci respectively for 6 comorbidities and 12 CM disease 'subtypes' without a relevant comorbidity. Genetic correlation analysis revealed that some subtypes may be biologically distinct from others. Further Mendelian randomization analysis showed differential causal effects of different subtypes to relevant complications. For example, we found that obese T2DM is causally related to increased risk of CAD (P = 2.62E-11). AVAILABILITY AND IMPLEMENTATION: R code is available at: https://github.com/LiangyingYin/CombGWAS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Health self-management experiences of colorectal cancer patients in postoperative recovery: A qualitative study.

PURPOSE: Health self-management helps improve health-related quality of life and life satisfaction, as well as cancer survival. The study aim was to explore the essence of the health self-management experiences and support needs of colorectal cancer patients after surgeries. METHODS: The study was based on phenomenology research methodology. Purposive sampling was used to obtain a heterogeneous sample to provide rich information regarding the research questions. Participants were recruited from colorectal surgery outpatient clinics in a hospital in Taiwan. Data were collected by semi-structured in-depth interviews and analyzed by thematic content analysis. Strategies adapted from Lincoln and Guba were used to enhance the trustworthiness of the study. RESULTS: Ten participants, 5 males and 5 females, were interviewed. Their health self-management experience fell into 3 overarching themes and 9 related subthemes. Our results show that (1) seeking support when experiencing discomfort, (2) when life changes, re-adjust accordingly, and (3) staying positive and self-perseverance are the essences of the health self-management experiences and support needs of postoperative colorectal cancer patients. CONCLUSIONS: Postoperative colorectal cancer patients experienced tremendous physical and psychosocial challenges after returning home from the hospital. Although burdened with multiple stressors, these patients were able to seek support, learning to practice self-care, facing cancer positively, and exhibit positive growth in life. Patients with colorectal cancer have to constantly adjust to the impacts of their diseases. The study results may provide as a reference for supporting postoperative adjustment and promoting health self-management among patients with colorectal cancer.